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Calicheamicin Antibody-Drug Conjugates for Liquid and Solid Tumor Indications

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Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Antibody-drug conjugates (ADCs) for solid tumor indications have traditionally employed microtubule disrupting agents. We recently demonstrated utility of calicheamicin, a double-strand DNA break inducing payload, when conjugated to an antibody targeting a cell surface antigen expressed on the surface of cancer stem cells (CSCs) or tumor-initiating cells (TICs) and Ephrin-A4 (EFNA4). When tested in preclinical models of breast and ovarian cancer, the hydrazone linker-based calicheamicin conjugate (PF-06647263) displayed robust antitumor activity, and the compound is currently being evaluated for clinical benefit to cancer patients. Calicheamicin is a member of a highly potent enediyne class of deoxyribonucleic acid (DNA)-damaging cytotoxic natural products with a unique mechanism of action that involves scission of DNA. Two additional calicheamicin-based ADCs are in late-stage clinical development, including the ADC, inotuzumab ozogamicin, targeting CD22-positive, liquid tumors including NHL and ALL, and the CD33-targeting gemtuzumab ozogamicin, targeting AML.

The recent expansion of the utility of calicheamicin conjugates to solid tumors may have a broader impact on ADC development, as their mechanism of action leading to tumor cell death is entirely different from microtubule disrupting agents. In particular, calicheamicin impacts quiescent or dormant cells as well as cycling cells, whereas microtubule inhibitors impact only cycling cells. Herein, we review the mechanism and key pharmacological findings of calicheamicin conjugates targeting liquid and solid tumors and discuss potential areas for future development of calicheamicin conjugates.

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Authors and Affiliations

  1. 3260 B Bayshore Blvd, Brisbane, CA, 94005, USA

    Hans-Peter Gerber

  2. Bioconjugates Discovery and Development, Oncology Research Unit, Pfizer Worldwide Research and Development, 401 North Middletown Road, Pearl River, NY, 10965, USA

    Marc Damelin & Puja Sapra

Authors
  1. Hans-Peter Gerber
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  2. Marc Damelin
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  3. Puja Sapra
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Correspondence to Hans-Peter Gerber .

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Editors and Affiliations

  1. NBE-Therapeutics Ltd., Basel, Switzerland

    Ulf Grawunder

  2. Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Stefan Barth

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Gerber, HP., Damelin, M., Sapra, P. (2017). Calicheamicin Antibody-Drug Conjugates for Liquid and Solid Tumor Indications. In: Grawunder, U., Barth, S. (eds) Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins. Milestones in Drug Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-46877-8_4

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